During the last 18 years of funding of this program project, the only NIH supported program project focused on narcolepsy, we have made significant strides in understanding the pathophysiology of narcolepsy, as well as the physiology of normal sleep. Our discovery during the last funding period that most cases of human narcolepsy cataplexy are caused by hypocretin (also called orexin) deficiency significantly changed the sleep field. In this revised competitive renewal proposal, based on our recent discoveries, we have refocused our research efforts and recruited new members to expand the expertise of the Center. In this revised proposal, we have brought together a unique group of independent investigators working across disciplines toward a common goal. Based on the reviewers'critiques, we have removed two projects from our original proposal, leaving four projects and a core (Project A). The core (Project A) provides the necessary core resources to support research projects at the Stanford Center for Narcolepsy, most notably biological samples. The goal of Project B, directed by Dr. Terry Young at the University of Wisconsin, Madison is to determine the prevalence of narcolepsy without cataplexy using an epidemiological approach and to study its association with HLA and lypocretin deficiency. Project D, directed by Dr. Juliette Faraco, will use a zebrafish model to isolate novel genes regulating hypocretin and histamine neurotransmission. In Project F, directed by Dr. Luis de Lecea, the discoverer of hypocretins, is seeking to identify novel genes with preferential expression in hypocretin-containing cells;an accessory goal of this project will be to study the neuropathology of narcolepsy without cataplexy. Project E, directed by Dr. Joachim Hallmayer, will use a human genetic approach to identify novel narcolepsy susceptibility genes. Narcolepsy is a frequent and disabling neurological disorder affecting more than 1 in 2,000 Americans. Our recent findings have led to new diagnostic procedures but have not yet changed therapeutic options. Our aims are improved diagnosis, a better understanding of the narcolepsy pathophysiology and the discovery of new treatments, if not a cure for narcoleptic patients.